4,4-diphenylhexahydroazepine compounds

ABSTRACT

4,4-Diphenylhexahydroazepine and derivatives thereof have been found to be useful antidepressant agents in the treatment of psychic depression in mammals. 4,4-Diphenylhexahydroazepine hydrochloride has been found to be particularly promising as it is characterized by a good therapeutic index.

United States Patent Holava et al.

[54] 4,4-DIPHENYLHEXAHYDROAZEPINE COMPOUNDS [72] Inventors: Henry Michael Holava; Richard Anthony Partyka, both of Liverpool, N.Yv

[73] Assignee: Bristol-Myers Company, New York, NY.

[22] Filed: Mar. 9, 1970 [21] Appl. No.: 17,919

52 us. c1 ..260/239 B, 260/2393 R, 260/566 A,

260/590, 260/599, 260/618 R, 424 244 5 1 1m. Cl. ..C07d 41/04, C07d 41/06 58 1 Field at Search ..260/239 B, 293 R [56] References Cited UNITED STATES PATENTS 3,468,893 9/1969 Mizzoni ..260/293 [151 3,666,752 [451 May 30, 1972 OTHER PUBLICATIONS Carruthers et al., J. Chem. Soc. (London), 1965, pp. I653- 1658.

Primary xaminerAiton D. Rollins Attorney-Herbert W. Taylor, Jr., Robert E. Havranek, Richard H. Brink and James Magee, Jr.

[5 7] ABSTRACT 7 Claims, No Drawings 1 2 4,4-DIPHENYLHEXAHYDROAZEPINE COMPOUNDS COMPLETE DISCLOSURE BACKGROUND OF THE INVENTION This invention relates to new synthetic compounds of value as antidepressants in the treatment of psychic depression in 5 mammals, including man.

The compounds are characterized as having the formula 1. Field of the Invention This invention relates to chemical compounds useful as antidepressant agents in the treatment of psychic depression.

2. Description of the Prior Art I The compounds of the present invention are new and novel. 0 None of the prior art discloses, teaches or anticipates these 4 compounds or their biological activity.

The most pertinent art appears to be: 1. F. G. Bordwell and K. M. Wellman, J. Org. Chem. 28,

2544 (1963) which describes the starting material, 4,4- z diphenylcyclohexanone. 7 f l 2. US. Pat. No. 3,376,312, reports the compound I-hydrox- It I imin0-4,4-diphenylcyclohexane.

3. U.S. Pat. No. 2,683, I 45 reports compounds of the generic formula wherein R is hydrogen, (lower)alkyl, phenyl(lower)alkyl, (lower)-ali cyclic( lower)alkyl, di(lower)a.lkylamino(lower)alk 0 R2 yl, omega-hydroxy(l0wer)alkyl, (lower)alkynyl'or (lower)al- 1t2 kenyl, and the pharmaceutically acceptable nontoxic acid addition salts thereof. The term (lower)alkyl" as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from one to eight carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. Similarly, where the term (lower)" is used as part of the description of wherein R is a lower alkyl g p n R epr an y another group, e.g., (lower)alicyclic, it refers to the alkyl g p. Such as p y and Substituted P y and the acid portion of such group which is therefore as described above in dition salts thereof. The compounds are described as having a cqnnection i h (l jk d' h i l d h idepressor amion on arterial blood pressurecals as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

4. W. Carruthers and R. .lohnstone, J. Chem. Soc., 1653 l h l d do t L (1965 report the Preparation of the Compound The pharmaceutically acceptable nontoxic acid addition salts include the mineral acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate and phosphate, and the organic acid addition salts such as the marate, malate, mandelate, ascorbate and the like.

A preferred embodiment of the present invention is the compounds having the formula as a by-product of a reaction of their study. No biological activity is reported.

5. Other references describing phenyl substituted azepines are US. Pat. Nos. 2,666,050, 2,740,778, 2,740,777, 2,740,780 and 2,763,643. None of these references are anticipatory of the compound of the present invention. 1;

SUMMARY OF THE INVENTION R .I The 4,4-diphenylhexahydroazepines of the present invention are com ounds characterized by the formula wherein R is H, (lower)alkyl, phenyl(lower)alkyl, (lower)alicyclic-(lower)alkyl, di(lower)alkylamino(lower)alkyl, omega hydroxy(lower)-alkyl, (lower)alkenyl or (lower)alkenyl, and the pharmaceutically acceptable nontoxic acid addition salts thereof.

Another preferred embodiment of the present invention is the compounds of formula I wherein R is hydrogen, (lower )alkyl, (Iower)alicyclic(lower)alkyl, phenyl(lower)alkyl, di(lower)alltyl amino(lower)alkyl, propargyl or propenyl; and the pharmaceutically acceptable nontoxic acid addition salt N thereof.

A more preferred embodiment is the compounds of formula I wherein R is hydrogen, (lower)alkyl, propargyl, propenyl or (lower)- alicyclic(lower)alkyl; and a pharrnaceutically acwherein R is H, (lower)alkyl, phenyl(lower)alkyl, (lower) alceptable nontoxic acid addition salts thereof.

icyclic(lower)alkyl, di(lower)alkylamino(lower)alkyl, omega- A.further preferred embodiment is the compounds of forhydroxy(lower)all yl, (lower)alkynyl or (lower)alkenyl, and mula I wherein R is hydrogen or (lower)a1kyl; and a pharthe phannaceutically'acceptable nontoxic acid additional salts maceutically acceptable nontoxic acid addition salt thereof,

thereof. especially the hydrochloride salts.

maleate, acetate, citrate, 'succinate, benzoate, tartrate, fu-

are prepared by I I Q NH OH'HC1 V 1 base I, l: ()H

I] III Polyphosphoric III acid, (or an equivalent acid) (1) NaH 1 i v (2) R -CX R Va Q R Vb = I I LiAlHa Va or Vb hydrogen.

Alternatively, the compounds I may be prepared as follows;

R -i-X 5 L=0 VII I i H i j? LiAllIi wherein R and R are described elsewhere but not including hydrogen.

The objectives of the present invention have been achieved, by the provision according to the present invention, of the process for the synthesis of the compound having the fonnula which process comprises the consecutive steps of A. heating a compound having the formula with at least an equimolar quantity, but preferably about a 10 B. heating compound [II in polyphosporic acid or its equivalent at a temperature of about 75 C. to about 125 C. for a period of 5 to 60 minutes to produce a compound having the formula and wherein R is (lower)alkyl, phenyl(lower)alkyl, (lower)alicyclic-(lower)alkyl, di(lower)alkylamino(lower)alkyl, omega-hydroxy-( lower)alkyl, (lower)alkynyl or (lower)alkenyl; which process comprises the consecutive steps of A. treating a compound having the formula I 11 IV with at least an equimolar quantity, but preferably about a percent excess, of sodium hydride with the aid of heat, at a temperature of about 40 C. to about 80 C., in an inert organic solvent, preferably selected from the group consisting of dioxane, dimethylformamide, tetrahydrofuran, and diethyl ether, but most preferably dimethylformamide, followed by the addition of at least an equimolar quantity, but preferably up to about a 10 percent excess, of a compound having the formula in which X is chloro, bromo or iodo, R and R are (lower)-alkyl,phenyl(lower)alkyl, (lower)alicyclic(lower)alkyl, di- (lower)alkylarnino(lower)alkyl, (lower)alkenyl, (lower)-alkynyl or omega-hydroxy(lower)alkyl, R is also phenyl or (lower)-alicyclic; to produce a compound having the formula in which R and R are as described above but not including hydrogen; and

B. treating compound Va and Vb with at least an equimolar quantity, but preferably about a 10 percent excess, of lithium aluminum hydride in an inert solvent, preferably an anhydrous organic ether selected from the group v comprised of tetrahydrofuran, dioxane and diethylether, but most' preferably tetrahydrofuran, with or without the aid of heat, but preferably with heat, up to the reflux temperature of the solvent to produce compound VI.

The objectives of the present invention have also been achieved by the process for the synthesis of compounds having the formula in which R is (lower)alkyl, phenyl(lower)alkyl, (lower )alicyclic-( lower)alkyl, di( lower)alkylamino( lower)alkyl, omega-hydroxy-(lower )alkyl, (lower )alkenyl or (lower )alkynyl; which process comprises the consecutive steps of A. treating the compound having the formula with at least an equimolar quantity, but preferably up to a 10 percent excess, of an acylating agent having the formula in which X is chloro, bromo, iodo, R is (lower)alkyl, phenyl- (lower)alkyl, phenyl, (lower)alicyclic, (lower)alicyclic(lower)-alkyl, di(lower)alkylamino(lower)alkyl, (lower)alkenyl, omega-hydroxy(lower)alkyl, or (lower)alkynyl with or without the aid of heat, but preferably with the aid of heat up to the boiling point of the solvent system in an organic solvent, preferably benzene and an equimolar quantity of triethylamine to produce the compound having the formula VII in which R is as defined above; and

- B. treating compoundVll with at least an equimolar quantity, but preferably about a percent excess, of lithium aluminum hydride in an inert solvent, preferably an anhydrous organic ether selected from the group comprised of tetrahydrofuran, dioxane and diethylether, but most preferably tetrahydrofuran, with or without the aid of heat, but preferably with heat up to the reflux temperature of the solvent, to produce compound I.

The compounds of the instant invention are biologically active as antidepressants in mammals, including man.

The compounds of the present invention have been screened through a variety of pharmacological tests using acknowledged standards for comparison; desipramine and amitriptylamine.

The most potent compound of the series appears to be the compound having the formula The following chart compares the antidepressant effect of X with desipramine and amitriptylamine.

CHART] Effective Dose (mg/kg.)

Test X Desip- Amitriramine ptyline Lethal Dose (LDSO) mouse p0 245 675 337 Lethal Dose (LDSO) rat po 500 Motor stimulation po 80 100 100 Reserpine reversal, mouse po 3 3 5 S-Hydroxytryptophan (5-HTP) ln common with desipramine, X potentiated the action of exogenous catecholamines and reversed guanethidine blockade in the anesthetized cat nictitating membrane preparation. X did not have significant stimulant or anorectic activity in rodents.

The profile of X in laboratory animals is consistent with that of an antidepressant.

Chart ll tabulates the pharmacological effect of other compounds of the present invention in three different antidepressant tests.

Chart II Effective Dose (mg/kg.)

The tests performed are generally known in the art and are essentially standard tests to determine antidepressant activity. The tests may be generally summarized as follows:

LDSO Determined in groups of four mice using Weils method.

Motor Stimulation This is determined by subjective behavioral observation 1 and 3 hours after drug administration (Irwin. 5., 1968), Psychopharmacologica, 13, 222).

Reserpine Reversal Three hours after drug administration mice are given reserpine, 5 mgjkg. iv. This will induce ptosis and behavioral depression in control mice; antidepressants, monoamine oxidase inhibitors and some stimulants will present the appearance of these effects (Randall, L. O. and Bagdon, R. E. 1959), Ann N. Y. Acad. Sci., 80, 626).

5-HT? Potentiation injections of S-hydroxytryptophan, 50 mg./kg. ip., produce behavioral stimulation in mice. Potentiation of this response by test compounds indicates potential monoarnine oxidase inhibitory properties (Randal, L. O. and Bagdon, R. E. (1959), Ann N. Y. Acad. Sci., 80, 626).

Tetrabenazine Reversal Tetrabenazine methanesulfonate, 35 mg./kg. ip., produces ptosis, hypoactivity and a low limb position in rats. Clinically useful antidepressants will prevent these tetrabenazine effects. This is considered our most valuable test for the preliminary evaluation of potential antidepressants (Pletscher, A. (1959), Ann. N. Y. Acad. Sci., 80, 1039). V

Oxotremorine Hypothermia Oxotremorine, 0.3 mgJkg. ip. induces tremor, salivation, lacrimation and a drop in rectal temperature in mice. Antidepressants will prevent the drop in rectal temperature.

Reserpine Hypothermia Reserpine, 5 mgJkg. ip., causes a considerable fall in rectal temperature. Antidepressants, stimulants and monoamine oxidase inhibitors will reverse this hypothermia (Askeny B. 1963), Life Sci., 2, 725

Yohimbine Potentiation in the Dog Yohimbine, 0.5 mg./kg. iv., produces a characteristic behavioral stimulation in the dog and this is potentiated by clinically useful antidepressants but not stimulants (Sanghvi, 1. and Gershon, S. (1969), Life Sci., 8, 449).

The methods outlined are all modifications from the references cited.

1n the treatment of depression in animals, including man, the compounds of the present invention are administered orally and parenterally, in accordance with conventional procedures for the administration of antidepressants in an amount of from about 0.25 mg./kg./dose to 20 mg./kg./dose depending upon the route of administration. The preferred dosage for the compounds of the invention is in the range of about 0.25 to about 5 mg./kg./dose three to four times a day.

In particular, the oral dose in man of the compound 4,4- diphenylhexahydroazipine or the salt thereof is in the range of about 5 mg. to about 125 mg. three to four times a day, and most preferably in the range of 5 to 75 mg. three to four times a day.

Starting Materials 4,4-Dipheny1cyclohexan-1-one. w

A. Diphenylacetaldehyde: (Ref: Zimmerman and Schuster, J. Am. Chem. Soc., 84, 4527(1962 Hydrobenzoin was prepared by the reduction of benzil with sodium borohydride in 95 percent ethanol. In a large scale run, 867 g. of hydrobenzoin (85 percent yield), m.p. 137.5l41.0, was prepared in two batches from 1 kg. of benzil and 122 g. of sodium borohydride in 5.5 1. of ethanol. The hydrobenzoin above was dissolved in 3 l. of benzene to which was added 76 g. of p-toluenesulfonic acid. The mixture was heated to reflux and 167 ml. of water was collected in an azeotropic distillation apparatus over 2.5 hours. The mixture was heated at reflux for an additional 3 days. The organic solution was extracted with water and sodium bicarbonate solution and was dried over sodium sulfate. Benzene was removed in vacuo and the residue was distilled to give 447 g. (50 percent) of diphenylacetaldehyde, b.p. l43-l55 (0.65 mm.), n D 15873-15884 (reported n D 1.5876).

B. Diphenylcyclohex-2-en-l-one (Ref: Zimmerman and Schuster, .I. Am. Chem. Soc., 84, 4527( 1962)). An approx- I imately 40 percent aqueous solution of Triton B was prepared by adding sufficient water to a 40 percent solution of Triton B methoxide (benzyltrimethylammonium methoxide) in methanol (Matheson, Coleman and Bell) and distillation of the bulk of the methanol. In a typical run, the reagents were: 37.0 g. (0.19 mole) of diphenylacetaldehyde, 15.1 g. (0.21 mole) of methyl vinyl ketone (Pfizer), 31 ml. of aqueous Triton B solution (see above) and 125 ml. of t-butyl alcohol. The aldehyde and ketone were dissolved in the alcohol and the solution was cooled in ice. The base was added in small portions with shaking. If the mixture was not kept cool or if the base was added too rapidly, the mixture was found to darken considerably. With care, only slight darkening occurred. After 2 hours, ice was added and then ether. The layers were separated and the aqueous solution was extracted with ether. The ether extracts were extracted several times with water and were dried over sodium sulfate. The ether was removed in vacuo and the residue was taken up in sufficient hot ethanol and set aside to crystallize at room temperature. Rapid cooling inevitably led to separation of an oil. The first crop of slightly yellow crystals, after drying in vacuo, amounted to 18.87 g., m.p. 88.0-90.5. Concentration of the mother liquors afforded a second crop, 4.10 g., m.p. 88.0-9l.0. The total yield was 49.1 percent of theory.

Anal. calcd. for C d-1 60: C, 87.06; H, 6.50

Found: C, 86.59; 86.65; H, 6.46;

C. 4,4-Diphenylcyclohexanone (Ref: Bordwell and Wellman, J. Org. Chem, 28, p. 2549(1963)). 4,4-Diphenylcyclohex-Z-en-one (6.80 g., 0.0274 mole) and 1.09 g. of 10 percent palladium-on-carbon (Englehard Industries, Inc.) were combined in 50 ml. of acetic acid and shaken under 35-50 lb. of hydrogen until uptake ceased (about 6 min.) and for 3 min. longer. The solution was diluted with 40 ml. of ether and filtered through diatomaceous earth. The filter cake was washed with three 50-ml. portions of ether, and the filtrate was poured into 200 ml. of ether and 500 ml. of water. The ethereal layer was separated and washed with water and dilute sodium bicarbonate. After drying and concentrating 6.71 g. (0.0268 mole, 98 percent yield) of 4,4-diphenylcyclohexanone, m.p. 140142, was obtained. Recrystallization from heptane gave prismatic needles, m.p. l 43-l44; 11556.88 a.

Anal. calcd. for

Found: C, 86.56; H, 7.21.

Experimental EXAMPLE 1 1-l-Iydroximino-4,4-diphenylcyclohexane.

A mixture of 100 g. (0.40 mole) 4,4-diphenylcyclohexanone and 30.6 g. (0.44 mole) hydroxylamine hydrochloride in 475 ml. of pyridine was refluxed under anhydrous conditions with stirring for 3 hours. The reaction mixture was cooled and poured into an ice-water mixture and triturated until solid. The solid was filtered, washed with water and dried under vacuum over P 0 Recrystallization from acetonitrile afiorded the product 87 percent yield) with mp. l65166 C. A second crop was obtained with mp. 160161 C. The total yield was 95 percent.

EXAMPLE 2 5,5-Di henylhexahydroazepine-Z-one.

l-l-Iydroximino-4,4-diphenylcyclohexane (121 g., 0.456 mole) was added to 400 ml. of preheated polyphosphoric acid at 95 C. with vigorous stirring over a period of 6 minutes. The reaction temperature increased to and at solution occurred at which time the temperature increased to C. After stirring for 6 minutes, the hot reaction mixture was then poured over 2 liters of ice with vigorous stirring. The resulting mixture was made basic with concentrated Nl-LOH. Stirring was continued for 1.5 hours, adding additional NH OH until the aqueous phase remained basic. The resultant solid was dissolved in CI-lCl and washed with aqueous NH OH twice, water, brine and dried over sodium sulfate. The solution was filtered and evaporated to give crude product. 400 m1. of ethanol was added to the crude product and the mixture was heated on a steam bath until solution occurred. Skellysolve B (petroleum solvent, essentially n-hexane, b.p. 6268 C.) was added and the solution was cooled to produce a white crystalline product which was collected by filtration. This procedure afforded 82.6 percent yield of product with m.p. 194-197 C. A sample recrystallized from CH CN gave analytically pure product with m.p. l96197 C.

Anal. calc'd. for C H NO:

N, 5.28%. Found: C, 81.17%; H, 7.21%;

EXAMPLE 3 4,4-Diphenylhexahydroazepine hydrochloride.

5,5-Diphenylhexahydroazepine-Z-one (2.65 g., 0.01 mole) as a solid was added under anhydrous conditions to a suspension of 0.42 g. (0.01 1 mole) of LAH (lithium aluminum hydride) in 70 ml. of dry THF (tetrahydrofuran). The dry THF was prepared by distillation over LAl-l. The reaction mixture was refluxed under nitrogen for 22 hours. After cooling, 1 ml. of water per 0.5 g. of LAH and 0.8 ml. of 10 percent sodium hydroxide per 0.5 g. of LAB used was added with vigorous Anal. calcd. for C l- N-HCl: C, 75.15%; H, Cl, 12.32%. 7.71%; N, 4.87%;

Found: C, 75.06%; N, Cl, 12.50%. 7.96%; N, 4.90%;

EXAMPLE 4 l -Methy1-5 ,5 -diphenylhexahydroazepine-2-one.

Solid 5,5-diphenylhexahydroazepine-Z-one (5.3 g., 0.02 mole) was added under anhydrous conditions to a suspension of sodium hydride (0.85 g., 0.02 mole, 56.6 percent sodium hydride in mineral oil) in 40 m1. of redistilled DMF (dimethylformaindde). The suspension was heated to 60 C. with stirring for 45 minutes. The suspension was cooled and 1.4 ml. (0.02 mole) of methyl iodide was added. The mixture was stirred at room temperature for 3 hours and then poured into 150 ml. of water. The crystalline product was collected by filtration, washed with water and dried in vacuo over P to give 94 percent yield, m.p. l64-l66 C. A sample recrystallized from ethylacetate and Skelly B gave an analytical sample, m.p. 166168 C.

Anal. calcd. for C H NO: C, 81.68%; H, 7.58%;

Found: C, 81.87%; H, 7.87%;

EXAMPLE 5 l-Ethyl-S ,5-diphenylhexahydroazepine-Z-one.

The same procedure and work up as described in Example 4, using 5.3 g. (0.02 mole) of Nal-l (56.6 percent in mineral oil), 1.8 ml. (0.022 mole) of iodoethane in 40 ml. DMF and 0.85 g. (0.02 mole) of 5,5-diphenylhexahydroazepin-2-one afforded an 89 percent yield of the product. Recyrstallization from CH CN gave an analytical sample, m.p. l29l 3 1 C.

Anal. calcd. for

C H- NO: C, 81.87%; H, 7.90%;

N, 4.77%. Found: C, 82.15%; H, 8.16%;

EXAMPLE 6 Anal. calcd. for C H NO: C, 84.47%; H, 7.09%;

Found: C, 84.56%; H, 7.33%;

EXAMPLE 7 l -Methyl-4 ,4-diphenylhexahydroazepine hydrochloride hemihydrate.

The same procedure and work up as described in Example 3, using 4.39 g. (0.0157 mole) of l-methyl-5,5-diphenylhexahydroazepine-Z-one and 0.66 g. (0.0173 mole) of LAB in 70 ml. of THF afforded 97 percent yield of product after salt formation, mp. 175-179 C. It was recrystallized from CH CN- ether to give an analytical sample, mp. l76l 77 C.

Anal. calcd. for C H N-flcl rfi H O: C, 73.41%; H, 8.1 1%; N, 4.51%; Cl, 1 1.40%; KF, 2.9%.

Found: C, 73.37%; H, 7.87%;

N, 4.45%; CI, 1 1.47%; KF, 3.9%.

EXAlVlPLE 8 l-Ethyl-4,4-diphenylhexahydroazepine hydrochloride.

The same procedure and work up as described in Example 3, using 1.68 g. (0.0057 mole) of l-ethyl-5,5-diphenylhexahydroazepine-Z-one and 0.24 g. (0.0063 mole) of [All in 50 m1. of THF afforded 76.7 percent yield of product after salt formation, mp. 205-208 C. Recrystallization from ethanolether produced a product having a mp. of 209-21 1 C.

Anal. calc d. for C ,,H N-HCI: C, 76.04%; H,

8.30%; N, 4.44%, Found: C, 75.82%; H,

8.45%; N, 4.33%; CI, 11.16%.

EXAMPLE 9 l-Benzyl-4,4-diphenylhexahydroazepine hydrochloride.

The same procedure and work up as described in Example 3, using 3.84 g. (0.0108 mole) of l-benzyl-5 ,5-diphenylhexahydroazepine-Z-one and 0.45 g. (0.0119 mole) of LAB in 70 ml. of THF gave a 72.4 percent yield of product after salt formation and mp. 130-133 C. The melt resoliditied and then melted at 200222 C. The crude product was recrystallized from ethanol-ether to give mp. 219 2238 C. (with melting and resolidifying as above). The product was stirred in ethyl acetate and refluxed for 5 minutes, cooled, filtered, washed with ether, and dried under high vacuum on P 0 to give product with a mp. 221223 C.

Anal. calcd. for C H NHCl: C, 79.45%; H,

7.47%; N, 3.71%; Cl, 9.38%.

Found: C, 79.35%; H,

7.57%, N, 3.62%; Cl, 9.37%.

EXAMPLE l0 l-(2-Dimethylaminoethyl)-5,S-diphenylhexahydroazepine- 2-one hydrochloride.

Sodium hydride )0.85 g., 0.02 mole, 56.6 percent sodium hydride in mineral oil) was added to a solution of 5.3 g. (0.22 mole) of 5,5-diphenylhexahydroazepine-2-one in 50 ml. of freshly distilled DMF under anhydrous conditions. The mixture was allowed to stir at 60 C. for 1 hour. l-Chloro-2- dimethylaminoethane (3.0 g., 0.028 mole) was added to the reaction mixture and was heated with stirring at C. for 5 hours. The work-up was conducted as described in Example 4 and conversion of the base to the hydrochloride salt in ether afiorded a 50 percent yield of the crude product.

The crude product was stirred in water and basified with 5 percent sodium carbonate, extracted with ether, washed with brine, dried over Na SO,, filtered, and evaporated to dryness. The residue was dissolved in CH CN and saturated with HCl. The slow addition of ether gave the HCl salt of the product. Recrystallization from Cl-l CN-ether gave analytically pure sample, mp. 233.5234.5 C.

Anal. calcd. for

C H N OHCI C, 70.85%;

H, 7.84%; N, 7.51%; Cl, 9.53%.

Found: C, 70.60%;

H, 7.85%; N, 7.46%; Cl, 9.56%.

EXAMPLE 1 l 1-( 2-Dimethylaminoethyl)-4,4-diphenylhexahydroazepine dihydrochloride hydrate.

Anal. calc'd. for C H N,-2HC1-H,O: C, 63.91%; H,

7.80%; N, 6.78%; Cl, 17.15%; KF, 4.36%.

Found: C, 64.14%; H. 7.95%; N, 6.80%; CI, 16.99%; KF, 3.76%.

EXAMPLE l2 1-Cyanomethy1-4,4-diphenylhexahydroazepine.

A mixture of 7.54 g. (0.03 mole) of 4,4-dipheny1hexahydroazepine, 3.18 g. (0.03 mole) of sodium carbonate, and 2.5 g. (0.033 mole) of chloroacetonitrile in 60 ml. of dried, redistilled DMF was heated, with stirring, at 6065 C. for 4 hours under anhydrous conditions. The reaction mixture was then cooled and poured into 200 ml. of water and extracted with ether. The ether extracts were therrwashed with water, brine, dried over sodium sulfate, filtered, and evaporated to dryness. This procedure afforded 83 percent yield of produce with mp. 8589 C.

A sample was dissolved in CH CN-ether mixture and HCl was bubbled through. The HCl salt was filtered, washed with ether and dried. Recrystallization from CH CN-ether gave analytical sample, mp. 18 ll 83 C.

Anal. calc'd. for c r-r N -r-rcrz C, 73.49%; H,

10.85%. Found: C, 73.39%; H,

EXAMPLE l3 1-( Z-Propynyl )-4,4-diphenylhexahydroazepine hydrochloride.

A mixture of 3.77 g. (0.015 mole) 4,4-diphenylhexahydroazepine, 1.59 g. (0.015 mole) sodium carbonate and 2.02 g. (0.017 mole) of propargyl bromide in 50 ml. of dry DMF was heated under anhydrous conditions with vigorous stirring at 50-60 C. for 3 hours. Work-up as described in Example 12 afi'orded a 58 percent yield of product after salt formation in ether; mp. 180188 C. Recrystallization twice from ethanol-ether gave mp. 2082l0 C.

Anal. calc'd. for C H N'HCl: C, 77.40%;

H, 7.42%; N, 4.30%; Cl, 10.88%.

Found: C, 77.20%;

H, 7.53%; N, 4.20%; CI, 10.81%.

EXAMPLE 14 l-Phenylacetyl-4,4-diphenylhexahydroazepine.

Phenylacetyl chloride (2.62 g., 0.017 mole) was added to a solution of 3.77 g. (0.015 mole) of 4,4-dipheny1hexahydroazepine and 1.52 g. (0.015 mole) of triethylamine in 60 ml. of dry benzene under anhydrous conditions. The reaction mixture was refluxed with stirring for hours, then cooled, evaporated to dryness and the residue was dissolved in ether. The ether solution was washed with water, aqueous Nl-LOH, water, 5 percent HCl, water, and brine, and then dried over sodium sulfate, filtered and evaporated to dryness. The oily residue was used directly as is in Example 15 without further purification. The NMR (nuclear magnetic resonance), 1R (infrared) and VPC (vapor pressure chromatography) spectra data were consistent for the structure of the product.

4 EXAMPLE l5 l-Phenethyl-4,4-diphenylhexahydroazepine hydrochloride.

A solution of 5.5 g. (0.015 mole) 1-phenylacetyl-4,4- diphenylhexahydroazepine in 15 m1. of dry THF was added under anhydrous conditions to a suspension of 0.65 g. (0.017 mole) of LAl-l in 35 ml. of THF and the mixture was refluxed for 17 hours with stirring. Work-up as described in Example 3 afforded in 84 percent yield of the HCl salt, mp. l65l 71 C.

Recrystallization from CH CN-ether gave mp. l61-164 C.

Anal. calc'd. for C,,,H,,N-HC1: C, 79.67%;

H, 7.74%; N, 3.57%; Cl, 9.04%.

Found: C, 79.54%;

7.87%; N, 3.60%; Cl, 9.14%.

EXAMPLE l6 EXAMPLE 17 l-n-Butyl-4,4-diphenylhexahydroazepine hydrochloride.

The same procedure and work-up as described in Experiment 15 using 4.82 g. (0.015 mole) of l-butyryl-4,4-diphenylhexahydroazepine, 0.65 g. (0.017 mole) of LAH in 50 ml. of THF afforded a 97.5 percent yield of product after salt formation.

Recrystallization from CH CN-ether ple, mp. 198-20l C.

gave analytical sam- Anal. calc'd. for C H- N'HCI: C, 76.83%; H,

8.79%; N, 4.07%; Found: C, 77.01%; H.

8.98%; N, 4.01%; CI, 10.21%.

EXAMPLE 18 1-Cyclopropylcarbonyl-4,4-diphenylhexahydroazepine.

Cyclopropylcarbonyl chloride (1.72 g., 0.0165 mole) was added to a solution of 3.77 (0.015 mole) of 4,4-diphenylhexahydroazepine and 1.52 g. (0.015 mole) triethylamine in 60 m1. dry benzene under anhydrous conditions. The reaction mixture was refluxed for 4 hours with stirring, then cooled and evaporated to dryness in vacuo. The residue was dissolved in ether. The ether solution was washed with water, 5 percent bicarbonate, water, 5 percent HCl water, brine, dried over Na SO filtered, and evaporated to dryness. Addition of npentane and cooling afforded 93.4 percent yield of solid product. Recrystallization from cyclohexane-npentane gave mp. -l02 C. A sample recrystallized from ethanol-water gave analytically pure product, mp. 99-101 C.

Anal. calc'd. for

C H NO: c, 82.72%; H, 7.89%;

N, 4.38%. C, 82.52%; H, 7.88%; N, 4.37%.

EXAMPLE 19 Found:

Anal. calcd. for c H Nl-lclz C, 77.28%; H,

8.25%; N, 4.10%; CI. 10.37%.

Found: C, 77.50%; H,

We claim:

1. A compound having the formula wherein R is hydrogen, (lower)alkyl, phenylfloweflalkyl,

16 (lower )-alicyclic(lower)a.lkyl, di(lower)alkylamino( lower)alk yl, [omega-hydroxy(lower)alkyl,] (lower)alkenyl, or (lower)alkynyl; and the pharmaceutically acceptable nontoxic acid addition salts thereof.

2. The compounds of claim 1 in which R is hydrogen, (lower)alkyl, (lower)alicyclic(lower)alkyl, phenyl(lower)alkyl. di(lower)alkylamino(lower)alkyl, propargyl or propenyl; and a pharmaceutically acceptable nontoxic acid addition salt thereof.

3. The compounds of claim I in which R is hydrogen, (lower)alkyl, propenyl, propargyl or (lower )alicyclicflower )alkyl', and the pharmaceutically acceptable nontoxic acid addition salt thereof.

4. The compounds of claim 1 in which R is hydrogen or (lower)alkyl; and a pharmaceutically acceptable nontoxic acid addition salt thereof.

5. The hydrochloride salts of the compounds of claim 4.

6. 4,4-Diphenylhexahydroazepine.

7. The hydrochloride salt of the compound of claim 6.

zg gg g UNITED STATES PATENT OFFECE CERTIFICATE GF CGRREQHQN Patent No. 3, 66,752 Dated May 50, 1972 Inventor) Henry Michael Holava and. Richard Anthony Partyka It: is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Claim 1 should read as follows:

A compound. having the formula wherein R is hydrogen, (lower)a'lkyl, phenyl(lower)alkyl, (lower)- alicyclic(lower)alkyl, d1(lower)alkylamino(lower)alkyl, (lower)- alkenyl, or (lower)alkynyl; and the 'pharmaceutically acceptable nontoxic acid addition salts thereof.

Signed and sealed this 21st day of November 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOT'I'SCHALK aittesting Officer Commissioner of Patents J 

2. The compounds of claim 1 in which R is hydrogen, (lower)alkyl, (lower)alicyclic(lower)alkyl, phenyl(lower)alkyl, di(lower)alkylamino(lower)alkyl, propargyl or propenyl; and a pharmaceutically acceptable nontoxic acid addition salt thereof.
 3. The compounds of claim 1 in which R is hydrogen, (lower)alkyl, propenyl, propargyl or (lower)alicyclic(lower)alkyl; and the pharmaceutically acceptable nontoxic acid addition salt thereof.
 4. The compounds of claim 1 in which R is hydrogen or (lower)alkyl; and a pharmaceutically acceptable nontoxic acid addition salt thereof.
 5. The hydrochloride salts of the compounds of claim
 4. 6. 4,4-Diphenylhexahydroazepine.
 7. The hydrochloride salt of the compound of claim
 6. 